1-(3&#39;,4&#39;,methylenedioxyphenoxy)-2-amino alkanes



United States Patent U.S. Cl. 260-3405 6 Claims ABSTRACT OF THEDISCLOSURE Novel-1-phenoxy-2-amino-alkanes of the formula O NHR:

wherein R is selected from the group consisting of hydrogen and alkyl of1 to 3 carbon atoms and R is selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms and their optical antipodesand their nontoxic, pharmaceutically acceptable acid addition saltswhich compounds are useful for curbing appetities of warm-bloodedanimals.

PRIOR APPLICATION This application is a continuation-in-part applicationof our copending, commonly assigned patent application Ser. No. 681,582filed Nov. 8, 1967, which in turn is a continuation-in-part applicationof US. application Ser. No. 448,881, filed Apr. 16, 1965, now abandoned.

OBJECTS OF THE INVENTION It is an object of the invention to provide thenovel 1-phenoxy-2-amino-alkanes of Formula I and their acid additionsalts.

It is another object of the invention to provide novel anorexigeniccompositions.

It is a further object of the invention to provide a novel method ofcurbing appetities of warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The novel l-phenoxy-2-amino-alkanes of the invention areselected from the group consisting of compounds of the formula NHR2kHz-O wherein R is selected from the group consisting of hydrogen andalkyl of 1 to 3 carbons and R is selected from the group consisting ofhydrogen and alkyl of 1 t0 4 carbon atoms, and their optical antipodes,and their non-toxic, pharmaceutically acceptable acid addition salts.

Since the compounds of the Formula I possess anasymmetrically-substituted carbon atom, they accur as racemic mixtures,which may be separated into their optical antipodes by conventionalmethods.

3,475,455 Patented Oct. 28, 1969 The compounds embraced by Formula Iabove are bases and, therefore, form acid addition salts and especiallynontoxic, pharmacologically acceptable acid addition salts withinorganic or organic acids. Such acid addition salts may be prepared byconventional methods, such as by dissolving the free base compound in asuitable solvent and acidifying the solution with the desired acid.Examples of non-toxic pharmacologically acceptable acid addition saltsof the compounds of the Formula I are those formed with hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid,tartaric acid, citric acid, succinic acid, malic acid, maleic acid,2-furoic acid, 8-chlorotheophylline and the like.

The phenoxy-Z-amino-alkanes of Formula I may be prepared by a variety ofmethods as illustrated by the following methods.

METHOD A By subjecting a pheonoxy-alkanone of the formula on,Q-o-om-g-cm-m wherein R has the definition of Formula I to catalyticreduction, preferably with a nickel or platinum catalyst, in thepresence of a nitrogen compound of the formula NH R (III) wherein R hasthe definition of Formula I.

METHOD B By subjecting aphenoxy-alkanone of the Formula II,

wherein R has the definition of Formula I, to reductive amination with ahydride, preferably with a complex metal hydride such as sodiumborohydride, in the presence of a nitrogen compound of the Formula III.

METHOD C By reacting a phenoxy-alkanone of the Formula II, wherein R hasthe definition of Formula I with a nitrogen compound of the Formula IIIin the presence of formic acid, for instance, by using a formic acidsalt or a formyl compound of the nitrogen compound III.

The phenoxy-alkanones II used as starting materials in Methods A throughC may themselves be prepared according to conventional methods, such asfrom alkali metal phenolates and a-haloalkanones.

METHOD D B subjecting an oxide of the formula 0 0g, Q-o-om-g-omnn NOH(IV) wherein R, has the same meaning as in Formula I to catalyticreduction, preferably with a nickel or cobalt catalyst, and subsequentmonoalkylation of the free amino group to introduce the substituent R ifdesired by conventional methods.

METHOD E 3 METHOD F By subjecting an imine or Schiffs base of theformula wherein R and R have the same meanings as in Formula I to acatalytic reduction, preferably with a nickel, platinum or palladiumcatalyst.

METHOD G By reducing an imine or Schiffs base of the Formula V, whereinR and R have the definitions of Formula I, with a hydride, preferablywith a complex metal hydride such as sodium borohydride.

The starting compounds of the Formula V for Methods F and G maythemselves be prepared by known methods, such as by reacting aphenoxy-alkanone of the Formula II with a nitrogen compound of theFormula III, and need not be isolated from the reaction mixture prior touse in the reduction reactions of Methods F and G.

METHOD H By reacting a l-phenoxy-Z-halo-alkane of the formula CHz-O-0-CH OHCHz-R IIal (VI) where R, has the definition of Formula I and Halis halogen, with a nitrogen compound of the Formula III wherein all butone of the hydrogen atoms are preferably replaced by a protective group,such as benzyl, phthalyl and toluene-sulfonyl, which is readilyremovable by reduction or hydrolysis subsequent to the reaction.

In those cases where the above Methods A through H yield compounds ofthe Formula I where R is hydrogen, the free amino group may subsequentlybe monoalkylatedd by conventional methods.

The compounds according to the present invention have usefulpharmacological properties. More particularly, they exhibit a stronganorexigenic activity coupled with very low central stimulating activityin warmblooded animals, such as mice and rats.

The novel anorexigenic compositions without any appreciable centralnervous system stimulating activity of the invention are comprised of atleast one compound selected from the group consisting of 1-phenoxy-2-amino-alkanes of the formula 0 03a 0CHi(I]HCH R o NHR:

wherein R is selected from the group consisting of hydrogen and alkyl of1 to 3 carbon atoms and R is selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms and their optical antipodes,and their non-toxic, pharmaceutically acceptable acid addition salts anda major amount of a pharmaceutical carrier.

For pharmaceutical purposes the compounds of the invention, that is,those embraced by Formula I, their optical antipodes and non-toxic acidaddition salts of the racemic compounds and of the optical antipodes areadministered by the peroral or parenteral route, the peroral route beingpreferred, to warm-blooded animals as active ingredients in conventionaldosage unit compositions, i.e., compositions consisting essentially ofan inert pharmaceutical carrier and one dosage unit of the activeingredient, such as tablets, coated pills, powders, suspensions,solutions, suppositories, capsules and the like. One dosage unit of thecompounds used as active ingredients in accordance with the presentinvention is from 10 to 150 mgm., preferably 20 to mgm.

The novel method of the invention for curbing appetities in warm-bloodedanimals comprises administering to warm-blooded animals an anorexigeniceffective amount of at least one compound selected from the groupconsisting of 1-phenoxy-2-amino-alkanes of the formula wherein R isselected from the group consisting of hydrogen and alkyl of 1 to 3carbon atoms and R is selected from the group consisting of hydrogen andalkyl of 1 to 4 carbon atoms and their optical antipodes and theirnon-toxic, pharmaceutically acceptable acid addition salts. The usualeffective dose of the said compounds is 0.016 to 5 mg./kg., preferably0.16 to 2.5 mg./kg. of body weight of the warm-blooded animals. In thefollowing examples there are described several preferred embodiments toillustrate the invention. However, it should be understood that theinvention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 1-(3',4'-methylenedioxy-phenoxy)-2-amino-propane and its hydrochloride 10.5 gm. (0.05 mol) ofl-(3',4-methylenedioxyphenoxy)-acetonoxime were dissolved in 100 cc. ofmethanol and the solution was hydrogenated at 40 C. and 5 atmosphereswith Raney nickel as a catalyst. After the theoretical amount ofhydrogen had been adsorbed, the reaction mixture was filtered to removethe catalyst, and the methanol was distilled off in vacuo. The oilyresidue, raw 1 (3',4 methylenedioxy phenoxy)-2-aminopropane, was admixedwith ethereal hydrochloric acid, and the precipitate formed thereby wasseparated by vacuum filtration and recrystallized from a mixture ofmethanol and ether. 7.5 gm. of a substance having a melting point of197-198 C. were obtained. It was identified to be I-(3',4'-methylenedioxy-phenoxy)-2-aminopropane hydrochloride of theformula EXAMPLE II Using the procedure of Example I,l-(3',4'-methylenedioxyphenoxy)-2-methylamino propane hydrochloridehaving a melting point of -l52 C. was obtained.

EXAMPLE III EXAMPLE IV Using the procedure of Example I,l-(3',4-methylenedioxyphenoxy) 2 propylamino-propane hydrochloridehaving a melting point of l26-128 C. was obtained.

EXAMPLE V Using the procedure of Example I,1-(3,4-methylenedioxyphenoxy) 2 isopropylamino-propane hydrochloridehaving a melting point of 149-150 C. was obtained.

PHARMACEUTICAL EXAMPLES Example A Preparation: The mixture was suspendedin an appropriate solvent, for example water, and applied to the core bymeans of a spray gun.

Mg Example D (capsules) 1-(3',4' methylenedioxyphenoxy) 2 methyl- 5 Amixture consisting of 80 parts of 1-(3',4'-methyleneamino-propanehydrochloride 75-0 dioxyphenoxy)-2-amino-propane hydrochloride and 120Lactose 25- parts of cornstarch was filled into hard gelatine capsules.Sec. calcium phosphate 150.0 100 gm. ofl-(3,4-methylenedioxyphenoxy)-2-methyl- Cornstarch 206.0 amino-propanesulfate were admixed with 295 gm. of Colloidal silicic acid 12-0carboxymethylcellulose and 20 gm. of stearic acid and Stearic acid 4.0Soluble Starch 8D Example E p s kneaded thoroughly with a solution of 40gm. of cellulose T t l 480,0 15 acetatephthalate in 200 ml. of a mixtureof ethanol/ethylacetate (1:1) and granulated. From this granulate dragePreparation: The mixture of the active substance was kernels werepressed in the usual manner, which then granulated in the usual mannerwith the adjuvants, supwere coated with the aid of a sugar containing 5%polyporting agents and lubricants and compressed into tablets.vinyl-pyrrolidone-suspension in water.

Example B (tablets) PHARMACOLOGICAL DATA Mg. Using the test proceduresof I. Spengler and P. Waser 1-(3',4 methylenedioxyphenoxy) 2 isopropylinArch. exptl. Path u. Pharmakol. 237, 171 (1959), resp. amino propanehydrochloride 100.0 G. Karber, Arch., exptl. Path. u. Pharmakol. 162,480 Sec. calcium phosphate 150.0 (1931), the compounds of the followingtable were com- Collodial silicic acid 206.0 pared with2-phenyl-3,4-dimethyl-morpholine hydrochlo- Magnesium stearate 4.0 ride(a known appetite curber) for the curbin of food Soluble starch 8.0intake FED on rats and for their central nervous systern excitationactivity (Z-ED and toxicity (LD Total 480.0 mice. The results arereported in Table I.

TABLE I F-ED50, Z-EDm, LDBD, Z-ED/ mgJkg. mgJkg. ing/kg. F-ED1-(3,4-methylenedloxyphenoxy)-2-aminoropane. H01 13.0 210 1- 3,-methylenedioxyphenoxy)-2-methylaminopropane. H01 18. 0 155 290 8. 6Known compound 19.0 38.5 230 2.0

Preparation: The mixture of the active substance was granulated in theusual manner with the adjuvants, supporting agents and lubricants andcompressed into tablets.

Example C (dragees) 1-(3',4' methylenedioxyphenoxy) 2 ethylamino-propanehydrochloride 600 Sec. calcium phosphate 135.0 Corn starch 91.0Colloidal silicic acid 7.0 Stearic acid 4.0 Polyvinylpyrrolidone 3.0

Total 300.0

Preparation: The mixture of the active substance was granulated in theusual manner with adjuvants, supporting agents and lubricants andcompressed into tablets.

(b) Coating:

Polyvinylpyrrolidone 2.0 Talcum 50.0 Titanium dioxide 3.0 Gum arabic 4.0Sugar 71.0

Total 430.0

As can be seen from Table I, the compounds of the invention possess anexcellent appetite curbing activity with a very low central nervoussystem stimulating activity. The therapeutic index (ZED )/(FED is 3 to 5times greater for the compounds of the invention than that of the knownappetite curber.

Various modifications of the compositions and method of the inventionmay be made without departing from the spirit of scope thereof.

We claim:

1. A 1-(3,4'--;rnethylenedioxyphenoxy)-2-amino alkane selected from thegroup consisting of a compound having the formula wherein R is selectedfrom the group consisting of hydrogen and alkyl of 1 to 3 carbon atomsand R is selected from the group consisting of hydrogen and alkyl of 1to 4 carbon atoms and their optical antipodes, and their non-toxic,pharmaceutically acceptable acid addition salts.

2. A compound of claim 1 selected from the group consisting ofl-(3,4'-methylenedioxyphenoxy)-2-aminopropane, its optical antipodes andits non-toxic, pharmaceutically acceptable acid addition salts.

3. A compound of claim 1 selected from the group consisting ofl-(3',4-methylenedioxyphenoxy)-2-methylamino-propane, its opticalantipodes and its non-toxic, pharmaceutically acceptable acid additionsalts.

4. A compound of claim 1 selected from the group consisting of 1-3',4'-rnethylenedioxyphenoxy) -2-ethylamino-propane, its opticalantipodes and its non-toxic, pharmaceutically acceptable acid additionsalts.

5. A compound of claim 1 selected from the group consisting of1-(3',4'-methylenedioxyphenoxy)-2-propylamino-propane, its opticalantipodes and its non-toxic, pharmaceutically acceptable acid additionsalts.

6. A compound of claim 1 selected from the group consisting ofl-(3,4-methylenedioxyphenoxy) 2 isopropylamino-propane, its opticalantipodes and its nontoxic, pharmaceutically acceptable acid additionsalts.

References Cited UNITED STATES PATENTS 9/1960 Cook et a1. 260-34053/1961 Cook et a1. 260-3405 US. Cl. X.R. 424282

